This application represents a systematic detailed study of three important neuropeptide systems involved in regulation of the digestive system and other visceral organs. The investigations will focus on opioid peptides, tachykinins (substance P, substance K and others), and cholecystokinin (CCK). Emphasis throughout is on understanding of neuropeptide mechanisms of action relevant to their pharmacological effects, physiological roles, and biochemical characteristics. The central hypothesis is that neuropeptides function in both sensory and motor pathways in the brain, spinal cord and periphery to regulate physiological activity of the gastrointestinal tract, urinary bladder, blood vessels, and other visceral organs. The specific regulatory events initiated or modulated by individual neuropeptides reflect neurotransmitter actions at multiple receptor subtypes in multiple anatomical sites mediated by multiple molecular forms and involving multiple interactions with other regulatory substances. Because of the complexities of the neuropeptide actions and interactions, a comprehensive research program is required that simultaneously addresses mechanisms at multiple biological levels and employs multiple experimental approaches. Even with a large collaborative effort, not all peptides can be studied at once. We will focus on three specific peptide groups (opioids, tachykinins and CCK) thought to be involved in both sensory and motor components of visceral reflex pathways. Opioid peptides were chosen because they are known to exert powerful regulatory effects on gastrointestinal and bladder motility by actions at brain, spinal cord and intramural sites and because an array of pharmacological tools in available for their study (Table 1). Tachykinins are known to function in both sensory and motor pathways and to interact at multiple levels with opioid systems. Cholesystokinin (CCK) is heavily represented in sensory and motor pathways relevant to the gut and also appears to interact in specific ways with opioid systems.